Cis-diaminedichloroplatinum(II) (cisplatin) is widely used in cancer chemotherapy for treatment of solid tumors, including ovarian, testicular and head and neck, and is especially effective in combined chemotherapy against squamous cell carcinoma and small cell lung carcinoma (Sur, et al., 1983; Steerenberg, et al., 1987).
Antitumor activity of cisplatin results from the ability of the diaquo species to crosslink the N-7 guanine residue of DNA producing intrastrand and interstrand crosslinks. To display antitumor activity, platinum complexes require two cis amine or ammine functionalities having at least one hydrogen atom that will hydrogen-bond to the oxygen atoms of the DNA phosphate groups and two strongly-bound leaving groups, e.g., chloride.
Like other cancer chemotherapeutic agents, cisplatin is a highly toxic drug. The main disadvantages of cisplatin are its extreme nephrotoxicity, which is the main dose-limiting factor, its rapid excretion via the kidneys, with a circulation half life of only a few minutes, and its strong affinity to plasma proteins (Freise, et al., 1982).
Attempts to minimize the toxicity of the drug have included combination chemotherapy, synthesis of cisplatin analogues (Prestayko, 1991; Weiss, et al., 1993), immunotherapy and entrapment in liposomes (Sur, et al., 1983; Weiss, et al., 1993) and preparation of polymer-platinate conjugates (Bogdanov, Jr., et al., 1996; Filipova-Voprsalova, et al., 1991; Fuji, et al., 1996; Han, et al., 1994; Johnsson and Cavallin-Stahl, 1996; Fiebig, et al., 1996; Neuse, et al., 1995; Schechter, et al., 1989).
With respect to the synthesis of cisplatin analogues, numerous platinum analogues have undergone preclinical and clinical trials, however only cisplatin and carboplatin have been approved for routine clinical use (Prestayko, 1991; Weiss, et al., 1993). Many of the analogues show no significant improvement in therapeutic index when compared to cisplatin. Cisplatin and its analogues have other drawbacks. Many are inactive when administered orally, some have low solubility in water and most induce severe toxic side effects including renal disfunction, nausea and vomiting, myelosuppression and neurotoxicity.
With respect to the preparation of polymer-platinum conjugates, such conjugates have been proposed as an approach to increasing solubility and reducing systemic toxicity. Although several platinum-polymer systems have been reported (Bogdanov, Jr., et al., 1996; Filipova-Voprsalova, et al., 1991; Fuji, et al., 1996; Han, et al., 1994; Johnsson and Cavallin-Stahl, 1996; Fiebig, et al., 1996; Neuse, et al., 1995; Schechter, et al., 1989) none have so far entered clinical investigation and few have displayed significant benefit in vivo. Failure has been due to lack of biocompatibility, toxicity of the proposed carrier, lack of antitumor activity and other problems.